The human IQGAP protein family comprises three members, which, as scaffold proteins, play important roles in the regulation/modulation of cytoskeletal architecture and cell adhesion through binding to various effectors/regulators (1-4). Among these, IQGAP1 has been best characterized (3-6). This protein was initially identified in human osteosarcoma cells and consists of a 1,657-amino acid polypeptide with significant similarity to the Ras-related GTPase-activating (RasGAP) proteins (7). A unique structural feature of IQGAP proteins is their IQ domain, which contains about 25 amino acids and is found in diverse families of calmodulin-binding proteins. This motif is capable of effecting on intracellular Ca2+ signaling and a wide range of cellular activities. Some previous studies showed that IQGAP1 might be able to modulate the Ras→Raf→MEK→MAP kinase/ERK pathway (MAP kinase pathway) in certain cells, but it can also function independently of this mechanism (8-10). Overexpression of IQGAP1 was seen in certain cancers, suggesting a role of this molecule in human tumorigenesis (3, 4, 11-13). IQGAP3 may potentially also have such a role as it was shown to be involved in cell proliferation (2). IQGAP2 has been less well studied and may function as a tumor suppressor (4).
Follicular epithelial cell-derived thyroid cancer is a common endocrine malignancy (14). This cancer can be histologically classified into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and anaplastic thyroid cancer (ATC). PTC can be further classified into several variants or subtypes, including mainly conventional PTC (CPTC), follicular variant PTC (FVPTC), and tall cell PTC (TCPTC). A striking genetic alteration in PTC is the BRAF mutation, which plays an important oncogenic role through activation of the MAP kinase pathway (15-17). ATC is a rare but rapidly lethal cancer with aggressive invasion and metastasis. PTC and FTC are both differentiated thyroid cancers with a relatively indolent clinical course, but FTC is generally more invasive and aggressive than PTC except for certain types, such as TCPTC, which is also relatively aggressive (18, 19). FTC and FVPTC tend to display invasive behaviors, such as vascular invasion (20). It is not known whether IQGAP proteins play any role in thyroid tumorigenesis or whether it determines aggressiveness our outcome in other cancers. There is a continuing need in the art to obtain better tools for diagnosing, prognosing, and treating human cancers.